Phase II trial of neoadjuvant short-course radiotherapy followed by ivonescimab with or without chemotherapy in locally advanced rectal cancer (TRIUNITE-03).

TPS258 Background: Despite significant advances in combining immune checkpoint inhibitors with chemoradiotherapy for locally advanced rectal cancer (LARC), improving outcomes in patients with proficient mismatch repair/microsatellite stable (pMMR/MSS) disease remains a major challenge. Conventional neoadjuvant oxaliplatin-based chemotherapy is associated with considerable toxicity, particularly neurotoxicity, which often limits treatment continuity and remains a critical clinical concern. The recent REGINA trial demonstrated promising efficacy using a chemotherapy-free regimen comprising short-course radiotherapy (SCRT) combined with nivolumab and regorafenib, reporting notable pathological complete response (pCR) and major pathological response (MPR) rates in pMMR/MSS LARC patients. These results provide compelling support for dual VEGF/PD-1 inhibition combined with SCRT in a chemotherapy-free setting. Ivonescimab is a novel humanized bispecific antibody targeting both PD-1 and VEGF-A. Early-phase trials in non-small cell lung cancer (NSCLC) and metastatic colorectal cancer (mCRC) have shown promising efficacy and a manageable safety profile for ivonescimab, both as monotherapy and in combination with chemotherapy. This trial aims to evaluate the efficacy and safety of neoadjuvant SCRT followed by ivonescimab with or without chemotherapy in LARC, and to assess whether the chemotherapy-free regimen can improve complete response (CR) rates while reducing treatment-related adverse events. Methods: This is a randomized, open-label, multicenter, phase II trial. Key eligibility criteria include: (1) age 18-80 years; (2) histologically confirmed rectal adenocarcinoma; (3) Tumor lower edge located ≤12 cm from the anal verge; (4) locally advanced disease (cT3-4 and/or N+). Patients are randomized 1:1 to two arms: Arm A receives SCRT (25 Gy in 5 fractions) followed, after a 7-day interval, by two cycles of ivonescimab (20 mg/kg IV Q3W) plus CapeOX chemotherapy (oxaliplatin 130 mg/m² IV on day 1; capecitabine 850-1000 mg/m² orally twice daily on days 1-14). Arm B receives SCRT followed by ivonescimab monotherapy (20 mg/kg IV Q3W for two cycles). After neoadjuvant treatment, response is evaluated by pelvic MRI, endoscopy, and digital rectal examination. Subsequent management—total mesorectal excision or watch-and-wait—is determined by multidisciplinary evaluation. The primary endpoint is CR rate, defined as pCR plus sustained clinical complete response (cCR). Secondary endpoints include MPR rate , 3-year disease-free survival, overall survival, organ preservation rate, and safety. Biomarker analyses will explore correlates of treatment response. A total of 100 patients will be enrolled. Accrual began in February 2025 across multiple centers in China. Clinical trial information: NCT06718543 .